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Research by a team at the NIH has linked gastrointestinal stromal tumors (GIST) to shutdown in an enzyme that supplies oxygen to cells.


As explained in a news release, in some cases the enzyme's failure to function is due to errors in genes containing the information needed to make the enzyme; and in others, the cause remains unknown but is thought to be genetic.


Although most adults with GIST have mutations in the KIT and PDGFRA genes, which imatinib targets, these mutations generally do not occur in the very rare cases of pediatric GIST.


For the study, the researchers examined tissue from 34 GIST patients for mutations in the genes for succinate dehydrogenase, an enzyme that processes oxygen to obtain energy for cells. The search was narrowed to genes for that enzyme because earlier work showed that mutations in this enzyme are a hallmark of Carney Stratakis syndrome, a rare disorder in which individuals develop GIST and paraganglioma, which also affects cells of the nervous system.


A total of 12% of the GIST patients in the study had mutations in genes containing the information needed to make up the subunits of succinate dehydrogenase-specifically, defects in the B and C subunits.


Although the remaining patients did not have any of these mutations, succinate dehydrogenase in tissue from their tumors did not appear to be functioning, and cellular respiration was disrupted.


The team believes that undiscovered mutations account for the enzyme's failure to function, said the senior author, Constantine A. Stratakis, MD, DSc, Acting Director of the Division of Intramural Research at the NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development, who is also one of the researchers after whom Carney Stratakis syndrome was named.


"Tracing the roots of this disease to cellular respiration has yielded a promising lead on how GIST tumors might form," he said. "The finding may also lead to the development of treatments for GIST subtypes that have not responded to traditional therapies."


The first author of the study, which was published in the Proceedings of the National Academy of Sciences, was Katherine A. Janeway, MD, of Dana-Farber Cancer Institute and Children's Hospital.


Dr. Stratakis said that the next goal is to identify the other genes that control the normal cellular respiration process and determine if mutations in these genes play a role in cancer.